U.S. patent application number 11/295730 was filed with the patent office on 2006-07-20 for method for treating neuropathic pain and associated syndromes.
This patent application is currently assigned to Avigen, Inc.. Invention is credited to Kirk W. Johnson, Jennifer Shumilla, Lance Sultzbaugh.
Application Number | 20060160843 11/295730 |
Document ID | / |
Family ID | 36476178 |
Filed Date | 2006-07-20 |
United States Patent
Application |
20060160843 |
Kind Code |
A1 |
Johnson; Kirk W. ; et
al. |
July 20, 2006 |
Method for treating neuropathic pain and associated syndromes
Abstract
The present invention is directed to the use of ibudilast for
treating neuropathic pain.
Inventors: |
Johnson; Kirk W.; (Moraga,
CA) ; Sultzbaugh; Lance; (San Francisco, CA) ;
Shumilla; Jennifer; (San Mateo, CA) |
Correspondence
Address: |
ROBINS & PASTERNAK LLP
1731 EMBARCADERO ROAD
SUITE 230
PALO ALTO
CA
94303
US
|
Assignee: |
Avigen, Inc.
Alameda
CA
|
Family ID: |
36476178 |
Appl. No.: |
11/295730 |
Filed: |
December 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60634248 |
Dec 6, 2004 |
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60665276 |
Mar 25, 2005 |
|
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60716333 |
Sep 12, 2005 |
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Current U.S.
Class: |
514/303 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 9/10 20180101; A61P 21/00 20180101; A61P 31/18 20180101; A61P
25/00 20180101; A61K 31/4745 20130101; A61P 31/22 20180101; A61P
25/08 20180101; A61P 35/00 20180101; A61P 43/00 20180101; A61K
31/437 20130101; A61P 25/04 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/303 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745 |
Claims
1. A method of treating a mammalian subject suffering from
neuropathic pain, said method comprising: selecting a mammalian
subject experiencing neuropathic pain, and administering to said
subject an initial therapeutic dosage of ibudilast effective to
achieve a maximal plasma concentration of at least about 125 ng/ml
ibudilast, whereby as a result of said administering, the subject
experiences relief of said neuropathic pain.
2. The method of claim 1, wherein said administering step is
effective to achieve a maximal plasma concentration of at least 200
ng/ml ibudilast.
3. The method of claim 1, wherein said selecting step comprises
selecting a mammalian subject suffering from postherpatic
neuralgia, trigeminal neuralgia, and neuropathic pain associated
with a condition selected from the group consisting of herpes, HIV,
traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex
sympathetic dystrophy, complex regional pain syndrome, spinal cord
injury, sciatica, phantom limb pain, multiple sclerosis, and cancer
chemotherapeutic-induced neuropathic pain.
4. The method of claim 1, wherein said administering step comprises
systemically administering ibudilast.
5. The method of claim 4, wherein said ibudilast is administered by
a route selected from oral, intravenous, subcutaneous,
intramuscular, intraperitoneal, intranasal, and sublingual.
6. The method of claim 1, wherein said administering step comprises
centrally administering ibudilast by a route selected from
intrathecal, intraspinal and intranasal.
7. The method of claim 1, wherein said administering step comprises
administering a daily dosage of ibudilast selected from the group
consisting of from about: 30-300 mg, 30-200 mg, and about 30-100 mg
ibudilast daily.
8. The method of claim 7, wherein said administering step comprises
administering from about 30 mg to about 100 mg ibudilast daily.
9. The method of claim 7, wherein said administering comprises once
daily dosing.
10. The method of claim 7, wherein said administering comprises
twice or thrice daily dosing.
11. The method of claim 1, wherein said administering is over a
time course of at least about a week.
12. The method of claim 1, wherein said administering is over a
time course ranging from about one week to 50 weeks.
13. The method of claim 1, wherein said administering step is not
accompanied by administration of an anti-emetic.
14. The method of claim 1, whereby said subject is experiencing
allodynia, and said administering is effective to relieve allodynia
experienced by said subject.
15. The method of claim 1, wherein said administering is effective
to attenuate neuropathic pain experienced by said subject for up to
at least 16 hours post ibudilast administration.
16. The method of claim 1, wherein said administering step
comprises administering ibudilast in combination with an additional
agent effective for treating neuropathic pain.
17. The method of claim 16, wherein said additional agent possesses
a mechanism of action different from ibudilast.
18. The method of claim 17, wherein said additional agent is
selected from the group consisting of gabapentin, memantine,
pregabalin, morphine and related opiates, cannabinoids, tramadol,
lamotrigine, lidocaine, carbamazepine, duloxetine, milnacipran, and
tricyclic antidepressants.
19. A method of treating a mammalian subject suffering from
neuropathic pain, said method comprising: administering to said
subject a combination of ibudilast and an additional agent
effective for treating neuropathic pain, whereby as a result of
said administering, the neuropathic pain experienced by said
subject is attenuated by an amount greater than that achieved by
administering either agent alone.
20. Use of ibudilast for the preparation of a medicament for
treating neuropathic pain, wherein said medicament is administered
to a mammalian subject at an initial dosage effective to achieve a
maximal plasma concentration of at least 125 ng/ml ibudilast.
21. The use of claim 20, wherein the step of administering
comprises administering said medicament to a mammalian subject
experiencing postherpatic neuralgia, trigeminal neuralgia, and
neuropathic pain associated with a condition selected from the
group consisting of herpes, HIV, traumatic nerve injury, stroke,
post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex
regional pain syndrome, spinal cord injury, phantom limb pain,
multiple sclerosis, sciatica, and cancer-chemotherapeutic-induced
neuropathic pain.
22. The use of claim 20, wherein the step of administering the
medicament comprises systemic administration.
23. The use of claim 21, wherein the step of administering the
medicament is by oral, intravenous, subcutaneous, intramuscular,
intraperitoneal, intranasal, or sublingual administration.
24. The use of claim 20, wherein the step of administering the
medicament comprises central administration.
25. The use of claim 20, wherein the step of administering the
medicament is not accompanied by administration of an
anti-emetic.
26. The use of claim 20, for the preparation of a medicament for
treating allodynia, wherein the step of administering the
medicament is effective to attenuate allodynia experienced by said
subject.
27. The use of claim 20, wherein the step of administering the
medicament is effective to decrease the amount of neuropathic pain
experienced by said subject for up to at least 16 hours
post-ibudilast administration.
28. The use of claim 20, wherein the step of administering the
medicament comprises administration of ibudilast in combination
with an additional agent effective for treating neuropathic pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to each of
the following provisional applications: Provisional Application No.
60/634,248, filed Dec. 6, 2004; Provisional Application No.
60/665,276, filed Mar. 25, 2005, and Provisional Application No.
60/716,333, filed Sep. 12, 2005, the contents of which are
expressly incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates generally to methods for
treating neuropathic pain. In particular, the present invention
pertains to methods of treating or preventing neuropathic pain and
its associated symptoms by administration of ibudilast
(3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine).
BACKGROUND OF THE INVENTION
[0003] In recent years, pain management has become an area of
increasing focus in the medical profession, partly due to the
growing population of elderly, issues surrounding quality of life,
and the growing numbers of patients reportedly suffering from pain.
Pain is both a sensory and emotional experience, and is generally
associated with tissue damage or inflammation. Typically, pain is
divided into two general categories--acute pain and chronic pain.
Both differ in their etiology, pathophysiology, diagnosis, and most
importantly, treatment.
[0004] Acute pain is short term, and is typically of a readily
identifiable cause. Patients suffering from acute pain typically
respond well to medications. In contrast, chronic pain,
medically-defined as pain that lasts for 3-6 months or longer, is
often not associated with an obvious injury; indeed, patients can
suffer from protracted pain that persists for months or years after
the initial insult. While acute pain is generally favorably treated
with medications, chronic pain is often much more difficult to
treat, generally requiring expert care. Reportedly, according to
the American Chronic Pain Association, over 86 million Americans
suffer from chronic pain, and the management of chronic pain has
long been recognized as an unmet clinical need. Most chronic pain
is neuropathic in nature (also referred to as neuralgia).
Neuropathic pain can, for instance, manifest itself as burning,
stabbing, and shock-like sensations.
[0005] Unfortunately, neuropathic pain management is at best
inconsistent, and often times ineffective. This is in part due to
the subjective nature of pain, but also due to poor diagnosis,
especially when the chronic pain is not clearly associated with a
nerve injury or other insult. Moreover, few, if any, ethical drugs
have been prospectively developed for the treatment of chronic
pain. Instead, the current medications used to treat chronic pain
are "borrowed" from other diseases, most commonly antiepileptic
drugs and antidepressants.
[0006] Current first-line treatments for chronic pain include
opioids, analgesics such as gabapentin, and tricyclic
antidepressants. In the instance of opioids, when administered over
prolonged periods, undesirable side effects such as drug tolerance,
chemical dependency and even physiological addiction can occur. Of
treatment regimes currently available for chronic pain, at best,
approximately 30% are effective in significantly diminishing the
pain, and may lose their efficacy over time. Although numerous
pharmacological agents are available for the treatment of
neuropathic pain, a definitive therapy has remained elusive.
[0007] In instances in which treatment with a single agent proves
to be unsuccessful, combination therapy is often then explored as a
second line treatment. For example, such combination therapy may
employ administration of an opioid agent with an adjuvant
analgesic, although the relative doses of each are often subject to
prolonged trial and error periods. Oftentimes, triple drug therapy
is necessary. Such therapy generally involves a combination of
tricyclic antidepressants, anti-convulsants, and a systemic local
anesthetic. Patient compliance drops significantly, however, when
treatment requires the administration of multiple pharmacologic
agents. Recently, researchers reported the use of a combination of
morphine and gabapentin in a randomized study for controlling nerve
pain (Gilron, I., et al., New Eng. J of Medicine, Vol 352:1281-82,
No. 13, Mar. 31, 2005).
[0008] Moreover, it is not only important to consider overall pain
relief, but also the type of pain relief. For example, chronic pain
is typically viewed as allodynia or hyperalgesia. Allodynia is pain
sensation from a stimulus that is not normally painful. The
allodynia is typically caused by a physical stimulous and thus
referred to as tactile or mechanical allodynia. Hyperalegsia is an
exaggerated sensation from a stimulus that is normally painful. The
hyperalegsia can occur from a variety of stimuli, but commonly, a
patient's reaction to hot and cold stimuli is reported.
Importantly, physicians often report that the current drugs are
most effective at relieving hyperalgesia although most patients
complain from allodynia, particularly mechanical allodynia.
[0009] In addition to poor and/or inconsistent efficacy, these
medications have several other undesirable properties, such as
adverse events, duration of action, and complicated dosing and
titration regiments.
[0010] The most common side-effect of the non-opiate drugs is
sedation or somnolence. Based on data from the package inserts for
these drugs, as many as 20-30% of patients experience sedation. As
mentioned above, the population greatest at risk for chronic pain
are elderly. For the elderly, experiencing significant and
persistent sedation poses other risks, mainly locomotors function
impairment. Such locomotors function impairment can lead to falling
and the inability to perform many daily functions such as
driving.
[0011] The duration of action is also a limitation for most of the
leading therapies. This is particularly important as pain, and
especially nighttime pain, can lead to depression, insomnia and
other factors that impact the patient's overall quality of life. A
recent study suggests that patients with chronic pain and
concurrent major depression and insomnia report the highest levels
of pain-related impairment. This study also found that insomnia in
the absence of major depression is also associated with increased
pain and distress. (Wilson et al., Clin J Pain 2002 March-April;
18(2):77-83.). Therefore, achieving pain relief with a sufficient
duration to achieve relief through the night is an important factor
for neuropathic pain drugs. Pain-relief drugs such as gabapentin
are taken once or more during the night to achieve pain
relief--thus disturbing sleep and exacerbating the patient's
overall quality of life.
[0012] Finally, the dosing or titration of the leading drugs, such
as gabapentin, can be complicated. For example, the recommended
starting dose for gabapentin in adults with postherpetic neuralgia
is a single 300-mg dose on Day 1, 600 mg/day on Day 2 (divided
BID), and 900 mg/day on Day 3 (divided TID). If no relief is
obtained at these doses, the dose can subsequently be titrated up
as needed for pain relief to a daily dose of 1800 mg (divided TID).
In clinical studies, efficacy was demonstrated over a range of
doses from 1800 mg/day to 3600 mg/day with comparable effects
across the dose range." (Neurontin.RTM. Full U.S. Prescribing
Information). Other antiepileptic drugs and antidepressants have
similar dosing schedules which are similarly complicated,
discourage compliance, and increase the chances of incorrect dosing
and even overdosing. Further, discontinuing such drugs can also be
challenging. For instance, as stated on the Full U.S. Prescribing
Information for Neurontin.RTM. " . . . [A]s dose is reduced,
discontinued or substituted with an alternative medication, this
should be done gradually over a minimum of 1 week."
[0013] Neuropathic pain (NP) is generally thought of as a
maladaptive chronic condition in which pain originates from damaged
nerves, often yielding pain that is out-of-proportion to the extent
of injury. The damage can occur from a physical injury such as
trauma or from chemical injury such as chemotherapeutics (e.g.,
paclitaxol). Neuropathic pain of this type is an important
component of a number of syndromes of varying etiologies whose
common characteristic is the development of a prolonged and
profound pain state. Among these conditions are spinal cord injury,
post-herpetic neuralgia, diabetic neuropathy, phantom limb pain,
stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia,
reflex sympathetic dystrophy (RSD), complex regional pain syndrome
(CRPS), cancer-chemotherapeutic induced neuropathic pain, vertebral
disk rupture, trigeminal neuralgia, and others.
[0014] Recently, however, it has been recognized that neuropathic
pain can manifest itself in the absence of an identifiable nerve
injury. These indications include AIDS and mirror image pain. The
lack of any nerve injury but unmistakable chronic pain has led to
increased interest in the role of glial cells in the maintenance of
the neuropathic pain state. (Watkins and Maier (2004) Drug Disc.
Today: Ther. Strategies 1(1): 83-88). More specifically, recent
research has demonstrated that glial enhance the release of
neurotransmitters that relay pain information to the spinal cord,
and, even more striking, release substances that increase the
excitability of pain-responsive neurons in the spinal cord. These
substances, called pro-inflammatory cytokines, create and maintain
exaggerated or pathological pain responses. Blocking the activation
of glia reduces pro-inflammatory cytokines and reverses
pathological pain. To date, no therapeutics have been approved that
have a putative glial-attenuation mechanism for the treatment of
neuropathic pain. Molecules which are glial-attenuators may play an
important role in treating neuropathic pain.
[0015] The small molecule, ibudilast,
(3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine), is a
non-selective inhibitor of cyclic nucleotide phosphodiesterase
(PDE) (Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999)
35-92). Ibudilast also acts as an LTD4 antagonist, an
anti-inflammatory, a PAF antagonist, and a vasodilatatory agent
(Thompson Current Drug Reports). Ibudilast is thought to exert a
neuroprotective role in the central nervous system of mammals,
presumably via suppression of the activation of glial cells (Mizuno
et al. (2004) Neuropharmacology 46: 404-411). Ibudilast has been
widely used in Japan for relieving symptoms associated with
ischemic stroke or bronchial asthma. Marketed indications for
ibudilast in Japan include its use as a vasodilator, for treating
allergy, eye tissue regeneration, ocular disease, and treatment of
allergic ophthalmic disease (Thompson Current Drug Reports). In
recent clinical trials, its use in the treatment of multiple
sclerosis, an inflammatory disease of the central nervous system,
has been explored (News.Medical.Net; Pharmaceutical News, 2 Aug.
2005). While the use of ibudilast for a number of varying
indications has been reported to date, to the best of the
applicants' knowledge, its use in treating neuropathic pain and
conditions associated therewith, including allodynia, has
heretofore remained largely unexplored.
[0016] In light of the above shortcomings in current approaches for
treating chronic pain, there exists a need for improved
compositions and methods for treating pain, particularly
neuropathic pain and its associated symptoms, and more
specifically, neuropathic pain associated with certain conditions
such as fibromyalgia, among others. Such approaches should ideally
overcome one or more of the problems associated with existing
methods for treating chronic pain. The present invention meets
these needs.
SUMMARY OF THE INVENTION
[0017] The present invention relates to a novel approach to
treating neuropathic pain, and is based upon the surprising
discovery that neuropathic pain can be successfully treated or
prevented by administration of ibudilast. Using standard
neuropathic pain models, the inventors have discovered that the
systemic administration of ibudilast is effective in preventing and
attenuating, if not eliminating, chronic neuropathic pain, such as
that associated with various syndromes. In some instances,
administration of ibudilast can provide an effective treatment for
neuropathic pain-related conditions that are non-responsive to
existing therapies. Further, ibudilast has been found to be
effective in significantly attenuating mechanical allodynia for a
duration lasting overnight--thus offering a significant advantage
over existing chronic pain drugs such as gabapentin. Such durable
efficacy is uncommon for most neuropathic pain drugs.
[0018] Accordingly, in one aspect, the invention provides a method
of treating a mammalian subject suffering from neuropathic pain by
administering to the subject a therapeutically effective amount of
ibudilast.
[0019] In one embodiment, the method includes the step of selecting
a mammalian subject experiencing neuropathic pain, followed by
administering to the subject an initial therapeutic dosage of
ibudilast effective to achieve a maximal plasma concentration of at
least about 100 to 125 ng/ml ibudilast or higher, whereby as a
result of such administering, the subject experiences relief (i.e.,
attenuation or reduction, elimination, or reversal) of the
neuropathic pain.
[0020] Mammalian subjects suitable to be selected for treatment
include those suffering from postherpatic neuralgia, trigeminal
neuralgia, and neuropathic pain associated with a condition
selected from the group consisting of herpes, HIV, traumatic nerve
injury, stroke, post-ischemia, fibromyalgia, reflex sympathetic
dystrophy, complex regional pain syndrome, and
cancer-chemotherapeutic-induced neuropathic pain.
[0021] In one or more alternative embodiments, an initial
therapeutic dosage of ibudilast is one effective to achieve a
maximal plasma concentration of at least about 100, 125, 150, 175,
200, 225, 250, 275 or 300 ng/ml ibudilast.
[0022] In yet another embodiment of the method, ibudilast is
administered at a daily dosage amount ranging from about 30 mg to
200 mg daily, or from about 30 mg to 100 mg daily.
[0023] The therapeutic dosage amount may be achieved by
administration once daily (i.e., in a single dose), twice daily
(i.e., in two separate doses), three times daily, or may be
administered as multiple doses over a timecourse of several days,
weeks, or even months. Such administering is typically over a
duration of time effective to result in a dimunition, and ideally
elimination or even reversal, of neuropathic pain. Exemplary
durations of treatment include at least about one week, from 1 week
to 1 month, from two weeks to 2 months, up to about 6 months, up to
about 12 months or even longer. In one particular embodiment,
treatment lasts from about 1 week to about 50 weeks.
[0024] In a preferred embodiment of the treatment method, the
administering is over a duration of time effective to result in
elimination of the neuropathic pain.
[0025] Administration of ibudilast is effective, in yet another
embodiment, to decrease an amount of neuropathic pain experienced
by the subject for up to at least 16 hours post administration.
[0026] In yet another embodiment of the method, administration of
ibudilast is not accompanied by administration of an anti-emetic
agent.
[0027] In a further embodiment of the method, ibudilast is
administered in combination with at least one other agent effective
for treating pain. Such agents agents include gabapentin,
memantine, pregabalin, morphine and related opiates, cannabinoids,
tramadol, lamotrigine, carbamazepine, duloxetine, milnacipran, and
tricyclic antidepressants, among others. In a preferred embodiment,
the secondary agent for treating neuropathic pain is one having a
mechanism of action different from that of ibudilast.
[0028] In yet another embodiment, ibudilast, when administered
either singly or as part of a combination therapy, is administered
either systemically or centrally (e.g., by intrathecal
administration, i.e., into the cerebrospinal fluid surrounding the
spinal cord). Such administration of ibudilast provides a novel
mechanism to attenuate pathologically painful conditions,
potentially via suppression of glial activation.
[0029] According to yet a further embodiment, ibudilast is
administered systemically, e.g. via intravenous, subcutaneous,
oral, intranasal, sublingual or other systemic routes, to a
mammalian, e.g., human, subject for the treatment of neuropathic
pain, e.g., a neuropathic pain syndrome.
[0030] In another aspect, the invention provides a composition or
combination effective for treating neuropathic pain. The
composition comprises a combination of: (i) ibudilast, and (ii) at
least one additional agent effective for treating neuropathic pain,
where each of the components is either contained in a single
composition or dosage form (such as in an admixture), or is present
as a discrete or separate entity (e.g., in a kit).
[0031] A composition of the invention may optionally include one or
more pharmaceutically acceptable excipients.
[0032] In yet another aspect, the invention encompasses a kit
comprising a combination of medicaments for the treatment of
neuropathic pain or a related syndrome, comprising, (i) ibudilast,
and (ii) at least one additional agent effective for treating
neuropathic pain, for simultaneous, sequential or separate use.
[0033] Each of the herein-described features of the invention is
meant to apply equally to each and every embodiment as described
herein, unless otherwise indicated.
[0034] Additional objects, advantages and novel features of the
invention will be set forth in the description that follows, and in
part, will become apparent to those skilled in the art upon reading
the following, or may be learned by practice of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0035] FIG. 1 presents a time course and dose response for
attenuation of mechanical allodynia by intraperitoneal (i.p.)
administration of ibudilast twice daily in a rat chronic
constriction injury (CCI) model of neuropathic pain as described in
Example 1. Pain is indicated by 50% withdrawal threshold as
assessed by von Frey fibers. Data points represent the
mean+/-standard error. Sham with 35% PEG/saline (-.smallcircle.-);
CCI with 35% PEG400/saline (-.tangle-solidup.-); CCI with 10 mg/kg
ibudilast (...DELTA...); CCI with 7.5 mg/kg ibudilast
(-.box-solid.-); CCI with 2.5 mg/kg ibudilast (-.quadrature.-).
n=4/group in sham and .gtoreq.5/group for CCIs. *=p<0.05 from
vehicle control by Students t test.
[0036] FIG. 2 presents a time course and dose response for
attenuation of mechanical allodynia by oral ibudilast
administration in a rat chronic constriction injury model of
neuropathic pain as described in Example 1. Pain is indicated by
50% withdrawal threshold as assessed by von Frey fibers. Data
points represent the mean+/-standard error. Sham with vehicle
control (10% HCO-60, 10% PEG400, saline) (closed circle); CCI
vehicle control (open triangle); CCI 50 mg/kg ibudilast (closed
triangle). n.gtoreq.5/group. *=p<0.05 from vehicle control by
Students t test.
[0037] FIG. 3 presents a time course for attenuation of mechanical
allodynia following twice daily i.p. administration of ibudilast in
the rat Chung model of neuropathic pain, as measured by 50%
withdrawal threshold with von Frey fibers. Details of the
experiment are provided in Example 2. Data points include error
bars representing the mean+/-standard error. Sham 35% PEG/saline
(-.smallcircle.-); Sham 10 mg/kg ibudilast (...circle-solid...);
CCI 10 mg/kg ibudilast (-.DELTA.-). n.gtoreq.5/group.
[0038] FIGS. 4A and 4B presents a time course of mechanical
allodynia in rat models for taxol-induced neuropathic pain, as
measured by 50% withdrawal threshold. See Example 3. Ibudilast was
administered twice daily with allodynia measurement prior to the
morning ibudilast administration. FIG. 4A depicts the attenuation
of allodynia after taxol-induced neuropathy is fully established.
Data is the average of allodynia measurements in both hind paws.
Data points represent the mean+/-standard error: taxol+35%
PEG/saline (-.box-solid.-); taxol+7.5 mg/kg ibudilast (filled
circle). n.gtoreq.5/group for allodynic animals and .gtoreq.2 for
non-taxol normal controls. Mean value data points for ibudilast
group at days 22, 24 and 25 are statistically significantly
different from vehicle control by Students t test. FIG. 4B is a
separate study and depicts the prevention of the development of
allodynia when ibudilast administration (as per FIG. 4A) is
initiated when the cancer chemotherapy-induced neuropathy is just
beginning to develop (12.sup.th day after initiating taxol
treatment). Data points represent the mean+/-standard error of
allodynia measurements in hind limb. Non-taxol-treated, but taxol
vehicle-treated, controls then treated with PEG/saline vehicle
(triangle) or ibudilast (diamond) vs taxol-treated rats then
administered PEG/vehicle (black square) or ibudilast 7.5 mg/kg i.p.
BID (circle).
[0039] FIGS. 5A and 5B presents ibudilast plasma pharmacokinetics
and tissue distribution (5A) in the rat after intraperitoneal
administration (5A) or after oral gavage (5B) from two separate
studies as described in Example 4. Data points represent mean
concentrations of ibudilast for each timepoint in each
representative tissue. Plasma and tissues as indicated in inset
figure legend. N=3 rats/time point. PK parameters per WinNonlin
analysis as described.
[0040] FIG. 6 presents GFAP immunohistochemistry of lumbar spinal
cord sections from CCI vehicle control or ibudilast-treated rats.
On the eigth day following CCI surgery, rats received ibudilast
(7.5 mg/kg) or vehicle control (35% PEG400/saline) ip BID for 5
days. Slides depicted are representative of 4 animals analyzed for
each treatment group at 40.times. magnification. Left side=vehicle
control animal; Right side=ibudilast-treated.
DETAILED DESCRIPTION OF THE INVENTION
[0041] The practice of the present invention will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, and pharmacology, within the skill of the art. Such
techniques are explained fully in the literature. See, e.g.; A. L.
Lehninger, Biochemistry (Worth Publishers, Inc., current addition);
Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc.,
current addition); J. March, Advanced Organic Chemistry (McGraw
Hill, current addition); Remington: The Science and Practice of
Pharmacy, A. Gennaro, Ed., 20.sup.th Ed.; Goodman & Gilman The
Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L.
Limbird, A. Gilman, 10.sup.th Ed.
[0042] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby incorporated by
reference in their entirety.
Definitions
[0043] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
administration modes, patient populations, and the like, as such
may vary, as will be apparent from the accompanying description and
figures.
[0044] It must be noted that, as used in this specification and the
intended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a drug" includes a single drug as
well as two or more of the same or different drugs, reference to
"an optional excipient" refers to a single optional excipient as
well as two or more of the same or different optional excipients,
and the like.
[0045] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions described below.
[0046] "Pharmaceutically acceptable excipient or carrier" refers to
an excipient that may optionally be included in the compositions of
the invention and that causes no significant adverse toxicological
effects to the patient.
[0047] "Pharmaceutically acceptable salt" includes, but is not
limited to, amino acid salts, salts prepared with inorganic acids,
such as chloride, sulfate, phosphate, diphosphate, bromide, and
nitrate salts, or salts prepared from the corresponding inorganic
acid form of any of the preceding, e.g., hydrochloride, etc., or
salts prepared with an organic acid, such as malate, maleate,
fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate,
lactate, methanesulfonate, benzoate, ascorbate,
para-toluenesulfonate, palmoate, salicylate and stearate, as well
as estolate, gluceptate and lactobionate salts. Similarly salts
containing pharmaceutically acceptable cations include, but are not
limited to, sodium, potassium, calcium, aluminum, lithium, and
ammonium (including substituted ammonium).
[0048] "Active molecule" or "active agent" as described herein
includes any agent, drug, compound, composition of matter or
mixture which provides some pharmacologic, often beneficial, effect
that can be demonstrated in-vivo or in vitro. This includes foods,
food supplements, nutrients, nutriceuticals, drugs, vaccines,
antibodies, vitamins, and other beneficial agents. As used herein,
the terms further include any physiologically or pharmacologically
active substance that produces a localized or systemic effect in a
patient.
[0049] "Substantially" or "essentially" means nearly totally or
completely, for instance, 95% or greater of some given
quantity.
[0050] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not.
[0051] By "pathological pain" is meant any pain resulting from a
pathology, such as from functional disturbances and/or pathological
changes, lesions, burns and the like. One form of pathological pain
is "neuropathic pain" which is pain thought to initially result
from nerve damage but extended or exacerbated by other mechanisms
including glial cell activation. Examples of pathological pain
include, but are not limited to, thermal or mechanical
hyperalgesia, thermal or mechanical allodynia, diabetic pain, pain
arising from irritable bowel or other internal organ disorders,
endometriosis pain, phantom limb pain, complex regional pain
syndromes, fibromyalgia, low back pain, cancer pain, pain arising
from infection, inflammation or trauma to peripheral nerves or the
central nervous system, multiple sclerosis pain, entrapment pain,
and the like.
[0052] "Hyperalgesia" means an abnormally increased pain sense,
such as pain that results from an excessive sensitiveness or
sensitivity. Examples of hyperalgesia include but are not limited
to cold or heat hyperalgesia.
[0053] "Hypalgesia" (or "hypoalgesia") means the decreased pain
sense.
[0054] "Allodynia" means pain that results from normally
non-noxious stimulus to the skin or body surface. Examples of
allodynia include, but are not limited to, cold or heat allodynia,
tactile or mechanical allodynia, and the like.
[0055] "Nociception" is defined herein as pain sense. "Nociceptor"
herein refers to a structure that mediates nociception. The
nociception may be the result of a physical stimulus, such as,
mechanical, electrical, thermal, or a chemical stimulus.
Nociceptors are present in virtually all tissues of the body.
[0056] "Analgesia" is defined herein as the relief of pain without
the loss of consciousness. An "analgesic" is an agent or drug
useful for relieving pain, again, without the loss of
consciousness.
[0057] The term "central nervous system" or "CNS" includes all
cells and tissue of the brain and spinal cord of a vertebrate.
Thus, the term includes, but is not limited to, neuronal cells,
glial cells, astrocytes, cerebrospinal fluid (CSF), interstitial
spaces and the like.
[0058] "Glial cells" refer to various cells of the CNS also known
as microglia, astrocytes, and oligodendrocytes.
[0059] The terms "subject", "individual" or "patient" are used
interchangeably herein and refer to a vertebrate, preferably a
mammal. Mammals include, but are not limited to, murines, rodents,
simians, humans, farm animals, sport animals and pets.
[0060] The terms "pharmacologically effective amount" or
"therapeutically effective amount" of a composition or agent, as
provided herein, refer to a nontoxic but sufficient amount of the
composition or agent to provide the desired response, such as a
reduction or reversal of neuropathic pain. The exact amount
required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the condition being treated, the particular drug or drugs employed,
mode of administration, and the like. An appropriate "effective"
amount in any individual case may be determined by one of ordinary
skill in the art using routine experimentation, based upon the
information provided herein.
[0061] The term "about", particularly in reference to a given
quantity, is meant to encompass deviations of plus or minus five
percent.
[0062] "Treatment" or "treating" neuropathic pain includes: (1)
preventing pain, i.e. causing pain not to develop or to occur with
less intensity in a subject that may be exposed to or predisposed
to pain but does not yet experience or display pain, (2) inhibiting
pain, i.e., arresting the development or reversing pain, or (3)
relieving pain, i.e., decreasing the amount of pain experienced by
the subject.
[0063] By "treating existing pain" is meant attenuating, elieving
or reversing neuropathic pain in a subject that has been
experiencing pain for at least 24 hours, such as for 24-96 hours or
more, such as 25 . . . 30 . . . 35 . . . 40 . . . 45 . . . 48 . . .
50 . . . 55 . . . 65 . . . 72 . . . 80 . . . 90 . . . 96 . . . 100,
etc. hours. The term also intends treating pain that has been
occurring long-term, such as for weeks, months or even years.
Methods for Treating Neuropathic Pain
[0064] As described previously, the inventors have discovered
ibudilast to be surprisingly effective in the treatment of
neuropathic pain, e.g., neuropathic pain associated with certain
syndromes such as viral neuralgias (e.g., herpes, AIDS), diabetic
neuropathy, phantom limb pain, stump/neuroma pain, post-ischemic
pain (stroke), fibromyalgia, reflex sympathetic dystrophy (RSD),
complex regional pain syndrome (CRPS), cancer pain, vertebral disk
rupture, and trigeminal neuralgia, cancer-chemotherapy-induced
neuropathic pain, among others. Based upon results using standard
pain models as described herein, the inventors have found the
administration of ibudilast, which can be administered by various
means and as infrequently as once daily, to be surprisingly
effective in providing a measurable reduction in the severity of
neuropathic pain, and in particular, in providing a measurable
reduction in the severity if not reversal of certain types of
neuropathic pain such as mechanical allodynia. Additional features
of the invention are described herein.
Ibudilast
[0065] The methods of the invention for the treatment of
neuropathic pain are based upon administration of the molecule,
ibudilast. Ibudilast is a small molecule drug (molecular weight of
230.3) having the structure shown below. ##STR1##
[0066] Ibudilast is also found under ChemBank ID 3227, CAS #
50847-11-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its
molecular formula corresponds to C.sub.14H.sub.18N.sub.2O.
Ibudilast is also known by various chemical names including
2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)1-propanone;
3-isobutyryl-2-isopropylpyrazolo(1,5-a)pyridine]; and
1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one.
Other synonyms for ibudilast include Ibudilastum (Latin), BRN
0656579, KC-404, MN-166. Its brand name is Ketas.RTM.. Ibudilast,
as referred to herein, is meant to include any and all
pharmaceutically acceptable salt forms thereof, prodrug forms
(e.g., the corresponding ketal), solvates, and the like, as
appropriate for use in its intended formulation for
administration.
[0067] Ibudilast is a non-selective nucleotide phosphodiesterase
(PDE) inhibitor (most active against PDE-3 and PDE-4), and has also
been reported to have LTD4 and PAF antagonistic activities. Its
profile appears effectively anti-inflammatory and unique in
comparison to other PDE inhibitors and anti-inflammatory agents.
PDEs catalyze the hydrolysis of the phosphoester bond on the
3'-carbon to yield the corresponding 5'-nucleotide monophosphate.
Thus, they regulate the cellular concentrations of cyclic
nucleotides. Since extracellular receptors for many hormones and
neurotransmitters utilize cyclic nucleotides as second messengers,
the PDEs also regulate cellular responses to these extracellular
signals. There are at least eight classes of PDEs:
Ca.sup.2+/calmodulin-dependent PDEs (PDE1); cGMP-stimulated PDEs
(PDE2); cGMP-inhibited PDEs (PDE3); cAMP-specific PDEs (PDE4);
cGMP-binding PDEs (PDE5); photoreceptor PDEs (PDE6); high affinity,
cAMP-specific PDEs (PDE7); and high affinity cGMP-specific PDEs
(PDE9). Ibudilast acts to suppress inflammation via action on
inflammatory cells (e.g. glial cells) resulting in the suppression
of both pro-inflammatory mediator and neuroactive mediator release.
References related to the foregoing include the following:
Obernolte, R., et al. (1993) "The cDNA of a human lymphocyte
cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family"
Gene 129: 239-247; Rile, G., et al. (2001) "Potentiation of
ibudilast inhibition of platelet aggregation in the presence of
endothelial cells" Thromb. Res. 102: 239-246; Souness, J. E., et
al. (1994) "Possible role of cyclic AMP phosphodiesterases in the
actions of ibudilast on eosinophil thromboxane generation and
airways smooth muscle tone" Br. J. Pharmacol. 111: 1081-1088;
Suzumura, A., et al. (1999) "Ibudilast suppresses TNF.alpha.
production by glial cells functioning mainly as type III
phosphodiesterase inhibitor in CNS" Brain Res. 837: 203-212;
Takuma, K., et al. (2001) "Ibudilast attenuates astrocyte apoptosis
via cyclic GMP signaling pathway in an in vitro reperfusion model"
Br. J. Pharmacol. 133: 841-848.
[0068] As stated previously, a reference to any one or more of the
herein-described drugs, in particular ibudilast, is meant to
encompass, where applicable, any and all enantiomers, mixtures of
enantiomers including racemic mixtures, prodrugs, pharmaceutically
acceptable salt forms, hydrates (e.g., monohydrates, dihydrates,
etc.), solvates, different physical forms (e.g., crystalline
solids, amorphous solids), metabolites, and the like.
Method of Administration
[0069] As set forth above, the present invention is directed to a
method of treating a mammalian subject suffering from neuropathic
pain by administering a therapeutically effective dosage of
ibudilast. Such administering is effective to decrease the amount
of neuropathic pain experienced by the subject, i.e., to result in
a significant attenuation or even reversal of neuropathic pain, as
demonstrated in the accompanying Examples. Ibudilast is preferably
administered at an initial dosage level effective to achieve a
maximal plasma concentration (Cmax) of at least about 100 ng/ml,
125 ng/ml, 150 ng/ml, 175 ng/ml, 200 ng/ml, 225 ng/ml, 250 ng/ml,
or 300 ng/ml or greater. In a preferred embodiment, ibudilast is
administered at a dosage level effective to achieve a Cmax of at
least about 125 ng/ml. Even more preferably, an initial therapeutic
dosage of ibudilast correlating with detectable efficacy is one
associated with a Cmax of at least about 350, 400, 450, 500, 550,
600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300,
1400, 1500, 1600, 1700 or 1800 ng/ml or greater.
[0070] The method of the invention may, in certain instances,
comprise a step of selecting a subject experiencing neuropathic
pain prior to administering ibudilast thereto. Such subjects are
typically selected from those suffering from postherpatic
neuralgia, trigeminal neuralgia, and neuropathic pain associated
with a condition selected from the group consisting of herpes, HIV,
traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex
sympathetic dystrophy, complex regional pain syndrome, spinal cord
injury, phantom limb pain, multiple-sclerosis, sciatica, and cancer
or cancer-chemotherapeutic-induced neuropathic pain. In certain
instances, the neuropathic pain subject selected is one whose
native insulin production is non-impaired (i.e., is
non-diabetic).
[0071] As can be seen from the accompanying Examples, the method of
the invention is effective to not only significantly attenuate
neuropathic pain, for example, mechanical allodynia, but to even
reverse it. Soon after initial dosing, the administration of
therapeutically effective levels of ibudilast demonstrated
sustained efficacy--such that pain relief was long-lasting. Thus,
in contrast to many other neuropathic pain medications currently on
the market, administering of ibudilast is effective to result in
sustained attenuation of neuropathic pain for an overnight
duration. For example, a therapeutically effective dose of
ibudilast is effective to treat neuropathic pain for a duration of
up to at least 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16
hours, 18 hours or even 20 hours or greater. This once daily oral
efficacy observed in animals, which is expected to translate to
humans based on pharmacokinetic projections of a sustained release
form of ibudilast, would not be expected given the recommended
frequencies (BID or TID) for ibudilast in existing clinical
indications.
[0072] Ibudilast may also be administered in combination with an
additional agent effective for treating neuropathic pain. In a
preferred embodiment, such agent possesses a mechanism of action
different from ibudilast. Exemplary agents include gabapentin,
memantine, pregabalin, morphine and related opiates, cannabinoids,
tramadol, lamotrigine, lidocaine, carbamazepine, duloxetine,
milnacipran, and tricyclic antidepressants. As noted in Example 1,
the administration of ibudilast in combination with the exemplary
pain medication, morphine, did not adversely affect the opiate
neuropathic pain efficacy of morphine, nor did the
co-administration of morphine adversely impact the efficacy of
ibudilast. The combination therapy resulted in a therapeutic
efficacy that was greater than that demonstrated by either agent
when administered alone.
[0073] Ibudilast is also effective in not only attenuating
cancer-chemotherapeutic agent-induced neuropathy, but can also
prevent the development of such neuropathy, as shown in Example 3.
Examples of chemotherapeutic agents known to result in patient
neuropathy include taxol, vinblastine, and vincristine.
Administration of ibudilast is effective in attenuating or
reversing neuropathic pain associated with the administration of
such agents for the treatment of cancer.
[0074] Yet another advantage of the invention is the administration
of a therapeutically effective dosage of ibudilast for treating
neuropathic pain which surprisingly substantially avoids related
emesis in the subject, as might have been expected based upon the
therapeutic dosages administered. Accordingly, in one embodiment of
the invention, administration of ibudilast is not accompanied by
administration of an anti-emetic agent. That is to say, based upon
the animal models, it is expected that in certain instances,
efficacy is observed with a dosing regimen in humans that does not
result in emesis, or that causes emesis initially (i.e., the first
few times that ibudilast is administered), however, following such
an initial dosing period (lasting, 1, 2, 3, 4, or 5 days), emesis
no longer becomes an issue.
[0075] The method of the invention offers an additional advantage
over existing neuropathic pain therapies, since existing
neuropathic pain medications have sedation as a major side-effect,
while ibudilast does not.
[0076] Preferred methods of delivery of ibudilast-based therapeutic
formulations for the treatment of neuropathic pain include systemic
and localized delivery, i.e., directly into the central nervous
system. Such routes of administration include but are not limited
to, oral, intra-arterial, intrathecal, intraspinal, intramuscular,
intraperitoneal, intravenous, intranasal, and inhalation
routes.
[0077] More particularly, an ibudilast-based formulation of the
present invention may be administered for therapy by any suitable
route, including without limitation, oral, rectal, nasal, topical
(including transdermal, aerosol, buccal and sublingual), vaginal,
parenteral (including subcutaneous, intramuscular, intravenous and
intradermal), intrathecal, and pulmonary. The preferred route will,
of course, vary with the condition and age of the recipient, the
particular neuralgia-associated syndrom being treated, and the
specific combination of drugs employed.
[0078] One preferred mode of administration for delivery of
ibudilast is directly to neural tissue such as peripheral nerves,
the retina, dorsal root ganglia, neuromuscular junction, as well as
the CNS, e.g., to target spinal cord glial cells by injection into,
e.g., the ventricular region, as well as to the striatum (e.g., the
caudate nucleus or putamen of the striatum), spinal cord and
neuromuscular junction, with a needle, catheter or related device,
using neurosurgical techniques known in the art, such as by
stereotactic injection (see, e.g., Stein et al., J Virol
73:3424-3429, 1999; Davidson et al., PNAS 97:3428-3432, 2000;
Davidson et al., Nat. Genet. 3:219-223, 1993; and Alisky and
Davidson, Hum. Gene Ther. 11:2315-2329, 2000).
[0079] A particularly preferred method for targeting spinal cord
glia is by intrathecal delivery, rather than into the cord tissue
itself.
[0080] Another preferred method for administering the
ibudilast-based compositions of the invention is by delivery to
dorsal root ganglia (DRG) neurons, e.g., by injection into the
epidural space with subsequent diffusion to DRG. For example, an
ibudilast-based composition can be delivered via intrathecal
cannulation under conditions where ibudilast is diffused to DRG.
See, e.g., Chiang et al., Acta Anaesthesiol. Sin. (2000) 38:31-36;
Jain, K. K., Expert Opin. Investig. Drugs (2000) 9:2403-2410.
[0081] Yet another mode of administration to the CNS uses a
convection-enhanced delivery (CED) system. In this way, ibudilast
can be delivered to many cells over large areas of the CNS. Any
convection-enhanced delivery device may be appropriate for delivery
of ibudilast. In a preferred embodiment, the device is an osmotic
pump or an infusion pump. Both osmotic and infusion pumps are
commercially available from a variety of suppliers, for example
Alzet Corporation, Hamilton Corporation, Alza, Inc., Palo Alto,
Calif.). Typically, an ibudilast-based composition of the invention
is delivered via CED devices as follows. A catheter, cannula or
other injection device is inserted into CNS tissue in the chosen
subject. Stereotactic maps and positioning devices are available,
for example from ASI Instruments, Warren, Mich. Positioning may
also be conducted by using anatomical maps obtained by CT and/or
MRI imaging to help guide the injection device to the chosen
target. For a detailed description regarding CED delivery, see U.S.
Pat. No. 6,309,634, incorporated herein by reference in its
entirety.
[0082] An ibudilast composition of the invention, when comprising
more than one active agent, may be administered as a single
combination composition comprising a combination of ibudilast and
at least one additional active agent effective in the treatment of
neuropathic pain. In terms of patient compliance and ease of
administration, such an approach is preferred, since patients are
often adverse to taking multiple pills or dosage forms, often
multiple times daily, over the duration of treatment.
Alternatively, albeit less preferably, the combination of the
invention is administered as separate dosage forms. In instances in
which the drugs comprising the therapeutic composition of the
invention are administered as separate dosage forms and
co-administration is required, ibudilast and each of the additional
active agents may be administered simultaneously, sequentially in
any order, or separately.
Dosages
[0083] Therapeutic amounts can be empirically determined and will
vary with the particular condition being treated, the subject, and
the efficacy and toxicity of each of the active agents contained in
the composition. The actual dose to be administered will vary
depending upon the age, weight, and general condition of the
subject as well as the severity of the condition being treated, the
judgment of the health care professional, and particular
combination being administered.
[0084] Therapeutically effective amounts can be determined by those
skilled in the art, and will be adjusted to the requirements of
each particular case. Generally, a therapeutically effective amount
of ibudilast will range from a total daily dosage of about 0.1 and
200 mg/day, more preferably, in an amount between 1-200 mg/day,
30-200 mg/day, 1-100 mg/day, 30-100 mg/day, 30-300 mg/day, 1-60
mg/day, 1-40 mg/day, or 1-10 mg/day, administered as either a
single dosage or as multiple dosages. Preferred dosage amounts
include dosages greater than about 10 mg BID or TID. That is to
say, a preferred dosage amount is greater than about 20 mg/day or
greater than 30 mg/day. Dosage amounts may be selected from 30
mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90
mg/day or 100 mg/day or more. Depending upon the dosage amount and
precise condition to be treated, administration can be one, two, or
three times daily for a time course of one day to several days,
weeks, months, and even years, and may even be for the life of the
patient. Illustrative dosing regimes will last a period of at least
about a week, from about 1-4 weeks, from 1-3 months, from 1-6
months, from 1-50 weeks, from 1-12 months, or longer.
[0085] Practically speaking, a unit dose of any given composition
of the invention or active agent can be administered in a variety
of dosing schedules, depending on the judgment of the clinician,
needs of the patient, and so forth. The specific dosing schedule
will be known by those of ordinary skill in the art or can be
determined experimentally using routine methods. Exemplary dosing
schedules include, without limitation, administration five times a
day, four times a day, three times a day, twice daily, once daily,
every other day, three times weekly, twice weekly, once weekly,
twice monthly, once monthly, and so forth.
Approaches for Treatment of Neuropathic Pain
[0086] Current pain therapies primarily target the neurons that
relay pain signals. These neurons are part of a long-described and
evolutionarily conserved pathway in vertebrates that transmits
signals from the periphery to the somatosensory cortex. A growing
body of literature suggests that neurons are not exclusive entities
in the development of persistent painful states (Watkins and Maier
(2003) Nat. Rev. Drug Discov. 2:973-85). Glial cells (microglia and
astrocytes) have been established as key participants of
neuropathic pain in well-established animal models (Wieseler-Frank
et al. (2004) Neurochem. Int. 45:389-95), and have been implicated
in human pathogenesis as well (Watkins and Maier (2002) Physiol
Rev. 82: 981-1011).
[0087] Several cues activate glia such as immune challenges,
infection and/or peripheral inflammation, and substances released
during prolonged neuron-to-neuron transmission (e.g.,
neurotransmitters, substance P, fractalkine, etc.). Glial function
is changed dramatically upon activation, resulting in elevated
release of neuroactive substances. In so doing, they also increase
the gain of neural transmission, amplifying the afferent signals
and hence exacerbating pain sensation.
[0088] Experimental evidence has demonstrated that glia activation
and subsequent events play a critical role in pain facilitation in
experimental animals. For example: (i) administration of
pro-inflammatory glial-activating cytokines such as
interleukin-1.beta. (IL-1.beta.) or tissue necrosis factor .alpha.
(TNF.alpha.) exacerbate underlying neuropathies; (ii)
pharmacological blockade of glial activation blocks and/or reverses
pain facilitation in every animal model examined; (iii) pain
facilitation can be blocked and/or reversed by the antagonism of
the neuroactive substances released by activated glia; (iv) pain
responses in normal animals are not affected by either the blockade
of glial activation or the antagonism of their pro-inflammatory
products; and (v) glial cells also release other neuroactive
substances including pro-inflammatory cytokines, excitatory amino
acids, and prostaglandins which can amplify neuropathic pain.
[0089] Ibudilast is a potent suppressor of glial activation (Mizuno
et al. (2004) Neuropharmacology 46: 404-411). In a dose-dependent
manner, ibudilast has been shown to suppress the production of
nitric oxide (NO), reactive oxygen species, interleukin
(IL)-1.beta., IL-6, and tumor necrosis factor (TNF) and enhance the
production of the inhibitory cytokine, IL-10, along with additional
neurotrophic factors including nerve growth factor (NGF),
glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in
activated microglia. Thus, ibudilast-mediated-neuroprotection was
found to be primarily due to the inhibition of inflammatory
mediators and the upregulation of neurotrophic factors.
[0090] Ibudilast crosses the blood-brain barrier when administered
systemically (Sugiyama et al. (1993) No To Shinkei 45(2):139-42;
FIG. 5), thus eliminating the need for more invasive methods of
administration in order to access central sites of inflammation
involved in neuropathic pain pathogenesis. Other known compounds
capable of attenuating glial activation include fluorocitrate and
minocycline, and they have shown efficacy in rodent models of
neuropathic pain. However, each is unacceptable for human therapy.
Fluorocitrate is unsuitable for human administration because it can
block glial uptake of excitatory amino acids (Berg-Johnsen et al.
(1993) Exp. Brain Res. 96(2):241-6), an essential function of glia
in the maintenance of normal CNS homeostasis. Minocycline, while
potentially useful in preventing glial activation, does not appear
to reverse extant glial pain facilitation (Raghavendra et al.
(2003) J. Pharmacol. and Exp. Therapeutics 306: 624-630). Hence,
this discovery of ibudilast efficacy for neuropathic pain following
systemic administration with well-tolerated dose levels represents
a unique therapy.
[0091] Taken together, glia and their pro-inflammatory products may
present opportunities for new strategies for pain control. Of the
substances released by activated glia, pro-inflammatory cytokines
(especially IL-10 and TNF.alpha.) are critical for this type of
pain facilitation. Thus, in accordance with yet another embodiment
of the invention, administration of ibudilast is effective to block
the release of pro-inflammatory cytokines.
Pain Models
[0092] The ability of ibudilast to treat neuropathic pain can be
evaluated by any of the standard pain models known in the art.
Examples of such models are as follows.
[0093] Carrageenan-induced Paw Hyperalgesia Model: The carrageenan
paw hyperalgesia test is a model of inflammatory pain. A
subcutaneous injection of carrageenan is made into the left
hindpaws of rats. The rats are treated with a selected agent
before, e.g., 30 minutes, the carrageenan injection or after, e.g.,
two hours after, the carrageenan injection. Paw pressure
sensitivity for each animal is tested with an analgesymeter three
hours after the carrageenan injection. See, Randall et al., Arch.
Int. Pharmacodyn. (1957) 111:409-419.
[0094] The effects of selected agents on carrageenan-induced paw
edema can also be examined. This test (see, Vinegar et al., J.
Phamacol. Exp. Ther. (1969) 166:96-103) allows an assessment of the
ability of a compound to reverse or prevent the formation of edema
evoked by paw carrageenan injection. The paw edema test is carried
out using a plethysmometer for paw measurements. After
administration of a selected agent, a carrageenan solution is
injected subcutaneously into the lateral foot pad on the plantar
surface of the left hind paw. At three hours post-carrageenan
treatment, the volume of the treated paw (left) and the un-treated
paw (right) is measured using a plethysmometer.
[0095] Von frey Filament Test: The effect of compounds on
mechanical allodynia can be determined by the von Frey filament
test in rats with a tight ligation of the L-5 spinal nerve: a model
of painful peripheral neuropathy. The surgical procedure is
performed as described by Kim et al., Pain (1992) 50 :355-363. A
calibrated series of von Frey filaments are used to assess
mechanical allodynia (Chaplan et al., J. Neurosci. Methods (1994)
53:55-63). Filaments of increasing stiffness are applied
perpendicular to the midplantar surface in the sciatic nerve
distribution of the left hindpaw. The filaments are slowly
depressed until bending occurred and are then held for 4-6 seconds.
The filament application order and number of trials were determined
by the up-down method of Dixon (Chaplan et al., supra). Flinching
and licking of the paw and paw withdrawal on the ligated side are
considered positive responses.
[0096] Chronic Constriction Injury: Heat and cold allodynia
responses as well as mechanical allodynia sensations can be
evaluated as described below in rats having a chronic constriction
injury (CCI). A unilateral mononeuropathy is produced in rats using
the chronic constriction injury model described in Bennett et al.,
Pain (1988) 33:87-107. CCI is produced in anesthetized rats as
follows. The lateral aspect of each rat's hind limb is shaved and
scrubbed with Nolvasan. Using aseptic techniques, an incision is
made on the lateral aspect of the hind limb at the mid-thigh level.
The biceps femoris is bluntly dissected to expose the sciatic
nerve. On the right hind limb of each rat, four loosely tied
ligatures (for example, Chromic gut 4.0; Ethicon, Johnson and
Johnson, Somerville, N.J.) are made around the sciatic nerve
approximately 1-2 mm apart. On the left side of each rat, an
identical dissection is performed except that the sciatic nerve is
not ligated (sham). The muscle is closed with a continuous suture
pattern with, e.g., 4-0 Vicryl (Johnson and Johnson, Somerville,
N.J.) and the overlying skin is closed with wound clips. The rats
are ear-tagged for identification purposes and returned to animal
housing.
[0097] Chung Model of Rat Neuropathic Pain: Heat and cold allodynia
responses as well as mechanical allodynia sensations can be
evaluated as described below in rats following spinal nerve injury
(e.g. ligation, transaction). Details are as initially described in
S H Kim and J M Chung, Pain (1992) 50:355-363.
[0098] The Hargreaves Test: The Hargreaves test (Hargreaves et al.,
Pain (1998) 32:77-88) is also a radiant heat model for pain. CCI
rats are tested for thermal hyperalgesia at least 10 days post-op.
The test apparatus consists of an elevated heated (80-82.degree.
F.) glass platform. Eight rats at a time, representing all testing
groups, are confined individually in inverted plastic cages on the
glass floor of the platform at least 15 minutes before testing. A
radiant heat source placed underneath the glass is aimed at the
plantar hind paw of each rat. The application of heat is continued
until the paw is withdrawn (withdrawal latency) or the time elapsed
is 20 seconds. This trial is also applied to the sham operated leg.
Two to four trials are conducted on each paw, alternately, with at
least 5 minutes interval between trials. The average of these
values represents the withdrawal latency.
[0099] Cold Allodynia Model: The test apparatus and methods of
behavioral testing is described in Gogas et al., Analgesia (1997)
3:111-118. The apparatus for testing cold allodynia in neuropathic
(CCI) rats consists of a Plexiglass chamber with a metal plate 6 cm
from the bottom of the chamber. The chamber is filled with ice and
water to a depth of 2.5 cm above the metal plate, with the
temperature of the bath maintained at 0-4.degree. C. throughout the
test. Each rat is placed into the chamber individually, a timer
started, and the animal's response latency was measured to the
nearest tenth of a second. A "response" is defined as a rapid
withdrawal of the right ligated hindpaw completely out of the water
when the animal is stationary and not pivoting. An exaggerated limp
while the animal is walking and turning is not scored as a
response. The animals' baseline scores for withdrawal of the
ligated leg from the water typically range from 7-13 seconds. The
maximum immersion time is 20 seconds with a 20-minute interval
between trials.
[0100] Additional information regarding models of neuropathic pain
is available in the following publications. Bennett G J, Xie Y K
(1988) "A peripheral mononeuropathy in rat that produces disorders
of pain sensation like those seen in man" Pain 33: 87-107; Chaplan
S R, Bach F W, Pogrel J W, Chung J M, Yaksh T L (1994)
"Quantitative assessment of tactile allodynia in the rat paw" J.
Neurosci. Meth. 53: 55-63; Fox A, Gentry C, Patel S, Kesingland A,
Bevan S (2003) "Comparative activity of the anti-convulsants
oxcarbazepine, carbamazepine, lamotrigin and gabapentin in a model
of neuropathic pain in the rat and guinea-pig" Pain 105: 355-362;
Milligan E D, Mehmert K K, Hinde J L, Harvey L O J, Martin D,
Tracey K J, Maier S F, Watkins L R (2000) "Thermal hyperalgesia and
mechanical allodynia produced by intrathecal administration of the
Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein,
gp120" Brain Res. 861: 105-116; De Vry J, Kuhl E, Franken-Kunkel P,
Eckel G (2004) "Pharmacological characterization of the chronic
constriction injury model of neuropathic pain" Eur. J. Pharmacol.
491:137-148. Polomano R C, Mannes A J, Clark U S, Bennett G J
(2001) "A painful peripheral neuropathy in the rat produced by the
chemotherapeutic drug, paclitaxel" Pain 94:293-304.
Formulations of the Invention
[0101] In addition to comprising ibudilast, a therapeutic
formulation of the invention may optionally contain one or more
additional components as described below.
[0102] Excipients/Carriers
[0103] In addition to ibudilast, the compositions of the invention
for treating neuropathic pain may further comprise one or more
pharmaceutically acceptable excipients or carriers. Exemplary
excipients include, without limitation, polyethylene glycol (PEG),
hydrogenated castor oil (HCO), cremophors, carbohydrates, starches
(e.g., corn starch), inorganic salts, antimicrobial agents,
antioxidants, binders/fillers, surfactants, lubricants (e.g.,
calcium or magnesium stearate), glidants such as talc,
disintegrants, diluents, buffers, acids, bases, film coats,
combinations thereof, and the like.
[0104] A composition of the invention may include one or more
carbohydrates such as a sugar, a derivatized sugar such as an
alditol, aldonic acid, an esterified sugar, and/or a sugar polymer.
Specific carbohydrate excipients include, for example:
monosaccharides, such as fructose, maltose, galactose, glucose,
D-mannose, sorbose, and the like; disaccharides, such as lactose,
sucrose, trehalose, cellobiose, and the like; polysaccharides, such
as raffinose, melezitose, maltodextrins, dextrans, starches, and
the like; and alditols, such as mannitol, xylitol, maltitol,
lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol,
myoinositol, and the like.
[0105] Also suitable for use in the compositions of the invention
are potato and corn-based starches such as sodium starch glycolate
and directly compressible modified starch.
[0106] Further representative excipients include inorganic salt or
buffers such as citric acid, sodium chloride, potassium chloride,
sodium sulfate, potassium nitrate, sodium phosphate monobasic,
sodium phosphate dibasic, and combinations thereof.
[0107] An ibudilast-containing composition of the invention may
also include an antimicrobial agent, e.g., for preventing or
deterring microbial growth. Non-limiting examples of antimicrobial
agents suitable for the present invention include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium
chloride, chlorobutanol, phenol, phenylethyl alcohol,
phenylmercuric nitrate, thimersol, and combinations thereof.
[0108] A composition of the invention may also contain one or more
antioxidants. Antioxidants are used to prevent oxidation, thereby
preventing the deterioration of the drug(s) or other components of
the preparation. Suitable antioxidants for use in the present
invention include, for example, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,
monothioglycerol, propyl gallate, sodium bisulfite, sodium
formaldehyde sulfoxylate, sodium metabisulfite, and combinations
thereof.
[0109] Additional excipients include surfactants such as
polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics such
as F68 and F88 (both of which are available from BASF, Mount Olive,
N.J.), sorbitan esters, lipids (e.g., phospholipids such as
lecithin and other phosphatidylcholines, and
phosphatidylethanolamines), fatty acids and fatty esters, steroids
such as cholesterol, and chelating agents, such as EDTA, zinc and
other such suitable cations.
[0110] Further, a composition of the invention may optionally
include one or more acids or bases. Non-limiting examples of acids
that can be used include those acids selected from the group
consisting of hydrochloric acid, acetic acid, phosphoric acid,
citric acid, malic acid, lactic acid, formic acid, trichloroacetic
acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid,
fumaric acid, and combinations thereof. Examples of suitable bases
include, without limitation, bases selected from the group
consisting of sodium hydroxide, sodium acetate, ammonium hydroxide,
potassium hydroxide, ammonium acetate, potassium acetate, sodium
phosphate, potassium phosphate, sodium citrate, sodium formate,
sodium sulfate, potassium sulfate, potassium fumerate, and
combinations thereof.
[0111] The amount of any individual excipient in the composition
will vary depending on the role of the excipient, the dosage
requirements of the active agent components, and particular needs
of the composition. Typically, the optimal amount of any individual
excipient is determined through routine experimentation, i.e., by
preparing compositions containing varying amounts of the excipient
(ranging from low to high), examining the stability and other
parameters, and then determining the range at which optimal
performance is attained with no significant adverse effects.
[0112] Generally, however, the excipient will be present in the
composition in an amount of about 1% to about 99% by weight,
preferably from about 5% to about 98% by weight, more preferably
from about 15 to about 95% by weight of the excipient. In general,
the amount of excipient present in an ibudilast composition of the
invention is selected from the following: at least about 2%, 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, or even 95% by weight.
[0113] These foregoing pharmaceutical excipients along with other
excipients are described in "Remington: The Science & Practice
of Pharmacy", 19.sup.th ed., Williams & Williams, (1995), the
"Physician's Desk Reference", 52.sup.nd ed., Medical Economics,
Montvale, N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical
Excipients, 3.sup.rd Edition, American Pharmaceutical Association,
Washington, D.C., 2000.
[0114] Other Actives
[0115] A formulation (or kit) in accordance with the invention may
contain, in addition to ibudilast, one or more additional active
agents effective in treating neuropathic pain. Preferably, the
active agent is one that possesses a mechanism of action different
from that of ibudilast. Such actives include gabapentin, memantine,
pregabalin, morphine and related opiates, cannabinoids, tramadol,
lamotrigine, carbamazepine, duloxetine, milnacipran, and tricyclic
antidepressants.
[0116] Gabapentin, also known as Neurontin.RTM., is structurally
related to the neurotransmitter GABA. Although structurally related
to GABA, gabapentin does not interact with GABA receptors, is not
converted metabolically into GABA or a GABA agonist, and is not an
inhibitor of GABA uptake or degradation. Gabapentin has no activity
at GABAA or GABAB receptors of GABA uptake carriers of the brain,
but instead interacts with a high-affinity binding site in brain
membranes (an auxiliary subunit of voltage-sensitive Ca.sup.2+
channels). The exact mechanism of action is unknown, only that its
physiological site of action is the brain. The structure of
gabapentin allows it to pass freely through the blood-brain
barrier. In vitro, gabapentin has many pharmacological actions
including modulating the action of the GABA synthetic enzyme,
increasing non-synaptic GABA responses from neural tissue, and
reduction of the release of several mono-amine neurotransmitters.
Daily dosages of gabapentin typically range from about 600 to 2400
mg/day, more preferably from about 900 to 1800 mg/day, and are
administered in divided doses, for example, three times a day.
Conventional unit dosage forms are 300 or 400 mg capsules or 600 or
800 mg tablets.
[0117] The active agent, memantine, is a receptor antagonist.
Memantine is believed to function as a low to moderate affinity
uncompetitive (open-channel) NMDA receptor antagonist which binds
to the NMDA receptor-operated cation channels. Recommended daily
dosage amounts typically range from about 5 mg to 20 mg.
[0118] The opiate, morphine, elicits its effects by activating
opiate receptors that are widely distributed throughout the brain
and body. Once an opiate reaches the brain, it quickly activates
the opiate receptors found in many brain regions and produces an
effect that correlates with the area of the brain involved. There
are several types of opiate receptors, including the delta, mu, and
kappa receptors. Opiates and endorphins function to block pain
signals by binding to the mu receptor site.
[0119] The cannabinoids, e.g., tetrahydrocannabinol, bind to the
cannabinoid receptor referred to as CB.sub.1. CB.sub.1 receptors
are found in brain and peripheral tissues; CB.sub.1 receptors are
present in high quantities in the central nervous system, exceeding
the levels of almost all neurotransmitter receptors. An additional
cannabinoid receptor subtype termed `CB2` has also been identified.
See, e.g., Martin, B. R., et al., The Journal of Supportive
Oncology, Vol. 2, Number 4, July/August 2004.
[0120] Although its mechanism of action has not yet been fully
elucidated, the opioid, tramadol, is believed to work through
modulation of the GABAergic, noradrenergic and serotonergic
systems. Tramadol, and its metabolite, known as M1, have been found
to bind to .mu.-opioid receptors (thus exerting its effect on
GABAergic transmission), and to inhibit re-uptake of 5-HT and
noradrenaline. The second mechanism is believed to contribute since
the analgesic effects of tramadol are not fully antagonised by the
.mu.-opioid receptor antagonist naloxone. Typical daily dosages
range from about 50 to 100 milligrams every 4 to 6 hours, with a
total daily dosage not to exceed 400 milligrams.
[0121] Lamotrigine is a phenyltriazine that stabilizes neuronal
membranes by blocking voltage-sensitive sodium channels, which
inhibit glutamate and aspartate (excitatory amino acid
neurotransmitter) release. The daily dosage of lamotrigine
typically ranges from 25 milligrams per day to 500 mg per day.
Typical daily dosage amounts include 50 mg per day, 100 mg per day,
150 mg per day, 200 mg per day, 300 mg per day, and 500 mgs per
day, not exceed 700 mgs per day.
[0122] Carbamazepine acts by blocking voltage-sensitive sodium
channels. Typical adult dosage amounts range from 100-200
milligrams one or two times daily, to an increased dosage of
800-1200 milligrams daily generally administered in 2-3 divided
doses.
[0123] Duloxetine is a potent inhibitor of neuronal uptake of
serotonin and norephinephrine and a weak inhibitor of dopamine
re-uptake. Typical daily dosage amounts range from about 40 to 60
milligrams once daily, or 20 to 30 milligrams twice daily.
[0124] Milnacipran acts as a serotonin and norepinephrine reuptake
inhibitor. Daily dosage amounts typically range from about 50 to
100 milligrams once or twice daily.
[0125] The dosage amounts provided above are meant to be merely
guidelines; the precise amount of a secondary active agent to be
administered during combination therapy with ibudilast will, of
course, be adjusted accordingly and will depend upon factors such
as intended patient population, the particular neuropathic pain
symptom or condition to be treated, potential synergies between the
active agents administered, and the like, and will readily be
determined by one skilled in the art based upon the guidance
provided herein.
[0126] Sustained Delivery Formulations
[0127] Preferably, the compositions are formulated in order to
improve stability and extend the half-life of ibudilast. For
example, ibudilast may be delivered in a sustained-release
formulation. Controlled or sustained-release formulations are
prepared by incorporating ibudilast into a carrier or vehicle such
as liposomes, nonresorbable impermeable polymers such as
ethylenevinyl acetate copolymers and Hytrel.RTM. copolymers,
swellable polymers such as hydrogels, or resorbable polymers such
as collagen and certain polyacids or polyesters such as those used
to make resorbable sutures. Additionally, ibudilast can be
encapsulated, adsorbed to, or associated with, particulate
carriers. Examples of particulate carriers include those derived
from polymethyl methacrylate polymers, as well as microparticles
derived from poly(lactides) and poly(lactide-co-glycolides), known
as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368;
and McGee et al., J. Microencap. (1996).
Delivery Forms
[0128] The ibudilast compositions described herein encompass all
types of formulations, and in particular, those that are suited for
systemic or intrathecal administration. Oral dosage forms include
tablets, lozenges, capsules, syrups, oral suspensions, emulsions,
granules, and pellets. Alternative formulations include aerosols,
transdermal patches, gels, creams, ointments, suppositories,
powders or lyophilates that can be reconstituted, as well as
liquids. Examples of suitable diluents for reconstituting solid
compositions, e.g., prior to injection, include bacteriostatic
water for injection, dextrose 5% in water, phosphate-buffered
saline, Ringer's solution, saline, sterile water, deionized water,
and combinations thereof. With respect to liquid pharmaceutical
compositions, solutions and suspensions are envisioned. Preferably,
an ibudilast composition of the invention is one suited for oral
administration.
[0129] In turning now to oral delivery formulations, tablets can be
made by compression or molding, optionally with one or more
accessory ingredients or additives. Compressed tablets are
prepared, for example, by compressing in a suitable tabletting
machine, the active ingredients in a free-flowing form such as a
powder or granules, optionally mixed with a binder (e.g., povidone,
gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent,
preservative, disintegrant (e.g., sodium starch glycolate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
and/or surface-active or dispersing agent.
[0130] Molded tablets are made, for example, by molding in a
suitable tabletting machine, a mixture of powdered compounds
moistened with an inert liquid diluent. The tablets may optionally
be coated or scored, and may be formulated so as to provide slow or
controlled release of the active ingredients, using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile. Tablets may optionally be provided with a
coating, such as a thin film, sugar coating, or an enteric coating
to provide release in parts of the gut other than the stomach.
Processes, equipment, and toll manufacturers for tablet and capsule
making are well-known in the art.
[0131] Formulations for topical administration in the mouth include
lozenges comprising the active ingredients, generally in a flavored
base such as sucrose and acacia or tragacanth and pastilles
comprising the active ingredients in an inert base such as gelatin
and glycerin or sucrose and acacia.
[0132] A pharmaceutical composition for topical administration may
also be formulated as an ointment, cream, suspension, lotion,
powder, solution, paste, gel, spray, aerosol or oil.
[0133] Alternatively, the formulation may be in the form of a patch
(e.g., a transdermal patch) or a dressing such as a bandage or
adhesive plaster impregnated with active ingredients and optionally
one or more excipients or diluents. Topical formulations may
additionally include a compound that enhances absorption or
penetration of the ingredients through the skin or other affected
areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl
myristate, and D-limonene, to name a few.
[0134] For emulsions, the oily phase is constituted from known
ingredients in a known manner. While this phase may comprise merely
an emulsifier (otherwise known as an emulgent), it desirably
comprises a mixture of at least one emulsifier with a fat and/or an
oil. Preferably, a hydrophilic emulsifier is included together with
a lipophilic emulsifier that acts as a stabilizer. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and/or fat make
up the so-called emulsifying ointment base which forms the oily
dispersed phase of cream formulations. Illustrative emulgents and
emulsion stabilizers include Tween 60, Span 80, cetostearyl
alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl
sulfate.
[0135] Formulations for rectal administration are typically in the
form of a suppository with a suitable base comprising, for example,
cocoa butter or a salicylate.
[0136] Formulations suitable for vaginal administration generally
take the form of a suppository, tampon, cream, gel, paste, foam or
spray.
[0137] Formulations suitable for nasal administration, wherein the
carrier is a solid, include a coarse powder having a particle size,
for example, in the range of about 20 to about 500 microns. Such a
formulation is typically administered by rapid inhalation through
the nasal passage, e.g., from a container of the powder held in
proximity to the nose. Alternatively, a formulation for nasal
delivery may be in the form of a liquid, e.g., a nasal spray or
nasal drops.
[0138] Aerosolizable formulations for inhalation may be in dry
powder form (e.g., suitable for administration by a dry powder
inhaler), or, alternatively, may be in liquid form, e.g., for use
in a nebulizer. Nebulizers for delivering an aerosolized solution
include the AERx.TM. (Aradigm), the Ultravent.RTM. (Mallinkrodt),
and the Acorn II.RTM. (Marquest Medical Products). A composition of
the invention may also be delivered using a pressurized, metered
dose inhaler (MDI), e.g., the Ventolin.RTM. metered dose inhaler,
containing a solution or suspension of a combination of drugs as
described herein in a pharmaceutically inert liquid propellant,
e.g., a chlorofluorocarbon or fluorocarbon.
[0139] Formulations suitable for parenteral administration include
aqueous and non-aqueous isotonic sterile solutions suitable for
injection, as well as aqueous and non-aqueous sterile
suspensions.
[0140] Parenteral formulations of the invention are optionally
contained in unit-dose or multi-dose sealed containers, for
example, ampoules and vials, and may be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, water for injections, immediately
prior to use. Extemporaneous injection solutions and suspensions
may be prepared from sterile powders, granules and tablets of the
types previously described.
[0141] A formulation of the invention may also be a sustained
release formulation, such that each of the drug components is
released or absorbed slowly over time, when compared to a
non-sustained release formulation. Sustained release formulations
may employ pro-drug forms of the active agent, delayed-release drug
delivery systems such as liposomes or polymer matrices, hydrogels,
or covalent attachment of a polymer such as polyethylene glycol to
the active agent.
[0142] In addition to the ingredients particularly mentioned above,
the formulations of the invention may optionally include other
agents conventional in the pharmaceutical arts and particular type
of formulation being employed, for example, for oral administration
forms, the composition for oral adminsitration may also include
additional agents as sweeteners, thickeners or flavoring
agents.
[0143] The compositions of the present invention may also be
prepared in a form suitable for veterinary applications.
Kits
[0144] Also provided herein is a kit containing at least one
combination composition of the invention, accompanied by
instructions for use.
[0145] For example, in instances in which each of the drugs
themselves are administered as individual or separate dosage forms,
the kit comprises ibudilast in addition to each of the drugs making
up the composition of the invention, along with instructions for
use. The drug components may be packaged in any manner suitable for
administration, so long as the packaging, when considered along
with the instructions for administration, clearly indicates the
manner in which each of the drug components is to be
administered.
[0146] For example, for an illustrative kit comprising ibudilast
and gabapentin, the kit may be organized by any appropriate time
period, such as by day. As an example, for Day 1, a representative
kit may comprise unit dosages of each of ibudilast and gabapentin.
If each of the drugs is to be administered twice daily, then the
kit may contain, corresponding to Day 1, two rows of unit dosage
forms of each of ibudilast and gabapentin, along with instructions
for the timing of administration. Alternatively, if one or more of
the drugs differs in the timing or quantity of unit dosage form to
be administered in comparison to the other drug members of the
combination, then such would be reflected in the packaging and
instructions. Various embodiments according to the above may be
readily envisioned, and would of course depend upon the particular
combination of drugs, in addition to ibudilast, employed for
treatment, their corresponding dosage forms, recommended dosages,
intended patient population, and the like. The packaging may be in
any form commonly employed for the packaging of pharmaceuticals,
and may utilize any of a number of features such as different
colors, wrapping, tamper-resistant packaging, blister paks,
dessicants, and the like.
[0147] It is to be understood that while the invention has been
described in conjunction with preferred specific embodiments, the
foregoing description as well as the examples that follow are
intended to illustrate and not limit the scope of the invention.
Other aspects, advantages and modifications within the scope of the
invention will be apparent to those skilled in the art to which the
invention pertains.
EXAMPLES
Example 1
Effect of Ibudilast on Mechanical Allodynia in a Rat CCI Model of
Neuropathic Pain
[0148] The effect of ibudilast on mechanical allodynia was assessed
in a rat chronic constriction injury (CCI) model of neuropathic
pain.
Methods.
[0149] Test Agents. Ibudilast was obtained as pure powder from
Sigma (St. Louis, Mo.) or Haorui Pharma (Edison, N.J.). It was
prepared daily as a solution for intraperitoneal (i.p.)
administration. An appropriate amount of ibudilast was dissolved in
100% polyethylene glycol (PEG) 400 (Sigma) and then diluted down to
a final concentration of 35% PEG400 in sterile saline (0.9% for
injection).
[0150] Test Article Administration. Ibudilast was administered at
2.5 mg/kg (0.9 ml/kg of 2.8 mg/ml in 35% PEG/saline), 7.5 mg/kg
(2.7 ml/kg of 2.8 mg/ml in 35% PEG/saline), or 10 mg/kg twice
daily, (3.7 ml/kg of 2.7 mg/ml in 35% PEG/saline) each morning
(typically 8 am) and pm (typically 3 pm). For oral efficacy
studies, ibudilast was administered at 50 mg/kg formulated in a
solution of 10% HCO-60, 10% PEG 400, saline, or could be
administered at 21-25.5 mg/kg (7-8.5 ml/kg of 3 mg/ml in 35%
PEG/saline) where attenuation of mechanical allodynia in rat CCI
was also observed. Drug stability and concentration were validated
by HPLC/MS/MS.
[0151] Animals. Pathogen-free adult male Sprague-Dawley rats
(280-350 g; Harlan Labs) were used in all experiments. Rats were
housed in temperature (23+/-3.degree. C.) and light (12:12 light:
dark; lights on at 0700 hr) controlled rooms with standard rodent
chow and water available ad libitum. Behavioral testing was
performed during the light cycle.
[0152] Chronic constriction injury (CCI): CCI was created at
mid-thigh level of the right hind leg. Four sterile, absorbable
surgical chromic gut sutures (cuticular 4-0, chromic gut, 27'',
cutting FS-2; Ethicon, Somerville, N.J.) were loosely tied around
the gently isolated sciatic nerve under isoflurane anesthesia
(Phoenix Pharm., St. Joseph, Mo.). The sciatic nerves of
sham-operated rats were exposed but not ligated. Suture placements
were typically verified at sacrifice by visual inspection.
Randomization to various treatment groups and initiation of dosing
occurred 7-8 days post-surgery.
[0153] Behavioral Measures von Frey Test. The von Frey test was
performed within the sciatic or saphenous innervation area of the
hindpaws. Briefly, a logarithmic series of 10 calibrated
Semmes-Weinstein monofilaments (von Frey hairs; Stoelting, Wood
Dale, Ill.) was applied randomly to the right hind paws to
determine the stimulus intensity threshold stiffness required to
elicit a paw withdrawal response. Log stiffness of the hairs is
determined by log.sub.10 (milligrams.times.10). The 10 stimuli had
the following log-stiffness values (values in milligrams are given
in parenthesis): 3.61 (407 mg), 3.84 (692 mg), 4.08 (1,202 mg),
4.17 (1,479 mg), 4.31 (2,041 mg), 4.56 (3,630 mg), 4.74 (5,495 mg),
4.93 (8,511 mg), 5.07 (11,749 mg), and 5.18 (15,136 mg). The range
of monofilaments used in these experiments (0.407-15.136 gm)
produces a logarithmically graded slope. Interpolated 50% response
threshold data is expressed as stimulus intensity in log.sub.10
(milligrams.times.10) or as gram fiber force. Assessments were made
prior to (baseline) and at specific times after intraperitoneal
drug administration. Behavioral testers were blinded to treatment
groups. Responses were used to calculate the 50% paw withdrawal
threshold (absolute threshold), by fitting a Gaussian integral
psychometric function using a maximum-likelihood fitting method and
this fitting method allows parametric statistical analyses.
Studies and Results
[0154] Dose Selection Study: Preliminary studies were designed to
assess rat tolerability to single and multiple intraperitoneal
administrations of ibudilast. Ibudilast i.p. doses>20 mg/kg
formulated in 35% PEG/saline administered at a volume</=5 ml/kg,
produced adverse behavioral effects in the rats that lasted up to 1
hr in duration. These included extended head, increased respiratory
rate, occasional circling behavior and vocalization, and lethargy.
Rats treated with vehicle alone at the same dose volumes did not
exhibit any adverse effects. In contrast, doses</=15 mg/kg ip
were generally well tolerated.
[0155] Acute Efficacy Study: Initially, a small set of animals
(n=3-4/group; groups=Sham controls, CCI vehicles, CCI ibudilast)
were tested for an acute reduction in allodynia following a single
i.p. administration of 10-15 mg/kg test agent. Mechanical allodynia
was measured at baseline (just prior to dosing) and 1, 2, 4, and 16
hr post-administration. Relative to the CCI vehicle animals, the
ibudilast-treated rats showed a reduction in allodynia. Allodynia
is defined as a painful withdrawal response to a normally innocuous
stimulus. This was apparent at +1 hr, maximum at +2 hr, and then
returned to baseline at 16 hr (data not shown, but see also FIG.
1). Importantly, there were no changes in paw withdrawal thresholds
in the ibudilast sham animals indicating that the neuropathic pain
efficacy in the CCI rats was not due to overt anesthesia.
[0156] Multi-day Study for Neuropathic Pain Efficacy: Given the
results of the preliminary acute study indicating transient
efficacy, a 1 week study was undertaken wherein the animals
(n=4/group for shams and 5-8/group for CCIs) were administered 2.5,
7.5, or 10 mg/kg ibudilast or 35% PEG/saline vehicle twice daily,
i.p., and mechanical allodynia was monitored at various time
intervals post-dosing. The +1 hr and +2 hr time points were
obtained following the am dose. A pre-dose test was conducted each
day .about.16 hr after the pm dose on the previous day in order to
assess durability of efficacy.
[0157] As shown in FIG. 1, ibudilast treatment attenuated the
magnitude of allodynia in the CCI rats. Notably, reversal was
biologically and statistically significant and consistently
manifested at +2 hr post-administration. Moreover, within two days
of this bid regiment, the effect was already becoming more
sustained for doses>2.5 mg/kg, such that reversal of neuropathic
pain was evident as long as 16 hr following ibudilast treatment.
Such durable efficacy is uncommon for most neuropathic pain drugs,
and would not necessarily be predicted from the pharmacokinetic
profile.
[0158] Study of Attenuation of Glial Cell Activation in
Ibudilast-Treated CCI Rats: At the end of the 5-day study, animals
(4/group) from the CCI vehicle control or CCI ibudilast group were
euthanized and lumbar spinal cord tissue was isolated and stained
for astrocyte activation with an antibody reactive against Glial
Fibrillary Acidic Protein (GFAP) as described in B A Winkelstein
and J A DeLeo, Brain Research (2002) 956:294-301. FIG. 6 depicts a
typical staining profile from CCI vehicle-treated animals. Enlarged
(activated) astrocytes, typically observed in subjects with
neuropathic pain (CCI rats in this case), are visible in the CCI
group. In contrast, a representative image from an
ibudilast-treated rat, which demonstrates good attenuation of
allodynia, is presented. Reduced glial cell activation as measured
by GFAP staining is observed in the ibudilast-treated
animal(s).
[0159] Oral Efficacy Study: A 5-day study was undertaken wherein
animals (n=8/group) were administered 21 mg/kg ibudilast or 35%
PEG/saline vehicle twice daily, p.o., for 2 days and then increased
to 25.5 mg/kg ibudilast for an additional 3 days. Pre- and post
mechanical allodynia testing was conducted at various time
intervals on days 1, 3, and 5. The +1 hr and +2 hr time points were
obtained following the am dose. A pre-dose test on these days was
also conducted in order to assess durability of efficacy.
Attenuation of allodynia was observed in ibudilast-treated animals
as early as 4 hr after the first dose and became durable (lasting
from pm dosing to next day's pre-am dosing test) following 2 days
of treatment (data not shown).
[0160] Efficacy in a 1 week study wherein ibudilast was
administered to rats (n.gtoreq.6/group) by oral gavage only once
daily (approximately 9 am) was also assessed. The vehicle
formulation was 10% HCO-60, 10% PEG400 in saline. As shown in FIG.
2, oral ibudilast administration significantly attenuated the
magnitude of allodynia in the CCI rats following 2 days of dosing
shortly after the morning dose and durable efficacy, lasting
overnight, was observed within 7 days of dosing.
[0161] Pharmacokinetics. Plasma Ibudilast Concentrations
Correlating with Efficacy: Dedicated pharmacokinetic studies in
normal rats were performed with ibudilast dosing i.p. or p.o. in
order to correlate drug plasma levels with changes in mechanical
allodynia (i.e. neuropathic pain efficacy). Following dosing (time
t=0), serial bleeding from n=3 rats/time point and 6 time points
interspersed between 5 min and 6 hr was obtained, plasma was
isolated, and ibudilast concentrations were determined by a HPLC
and two-dimensional mass spectrometry (LC/MS/MS) method (described
in Example 4) sensitive to .ltoreq.1 ng/ml. Maximal plasma
concentrations (Cmax) correlating with the first indications of
allodynia efficacy following ibudilast i.p. treatment in CCI
rats--i.e. 2.5 mg/kg--yielded maximal plasma concentrations
averaging 125 ng/ml. Significant efficacy in neuropathic pain was
observed at 7.5 mg/kg i.p. and correlated with maximal average
plasma concentrations of 1714 ng/ml. When administered orally at 21
mg/kg in PEG400/saline or 50 mg/kg in 10% HCO-60/10% PEG400/saline,
wherein clearly identifiable and statistically signifant efficacy
was observed, the average maximal plasma concentrations were 325
ng/ml (FIG. 5B) or 387 ng/ml, respectively. Moreover,
pharmacokinetic-pharmacodynamic analyses involving PK parameters
including Cmax, area under the curve (AUC), and elimination
half-life (t.sub.1/2) indicated Cmax is an important parameter in
establishing efficacy.
[0162] Combination Therapy Benefit with Morphine: A rat CCI
efficacy study was performed wherein 7.5 mg/kg ibudilast in 35%
PEG/saline administered ip bid was performed alone or in
combination with 1 mg/kg morphine administered s.c. over several
days of treatment. Reversal of allodynia in comparison to vehicle
control by morphine was greater than that by ibudilast and the
combination of morphine+ibudilast was better than either agent
alone. (Data not shown). Hence, ibudilast treatment in combination
does not interfere with opiate neuropathic pain efficacy, and vice
versa, and combined therapy efficacy is enhanced relative to either
agent alone. Similar results are expected with other neuropathic
pain drugs including gabapentin, cymbalta, etc.
Conclusions
[0163] In a classic, validated model (rat CCI) of neuropathic pain
wherein the primary efficacy endpoint was mechanical allodynia,
ibudilast administration systemically (i.p. or p.o.) at daily
frequency of once or twice daily markedly attenuated allodynia.
Additionally, it has been determined that ibudilast can be combined
with other neuropathic pain therapies such as morphine, where the
resulting neuropathic pain efficacy observed for the combination is
greater than that observed for either agent alone.
[0164] The plasma concentrations of systemically-administered
ibudilast which correlated with neuropathic pain efficacy
correlated with maximal plasma concentrations (Cmax).gtoreq.125
ng/ml, which is above the plasma concentrations typically observed
in asthma or post-stroke patients treated with ibudilast.
Recommended and most-practiced dosing regimens of ibudilast in
humans are 10 mg BID or TID, which yields single dose Cmax of 25
ng/ml (Ketas.sup.R Package Insert) or multi-dose steady state Cmax
of 45 ng/ml (Z Cai-Li et al., (2003) Acta Pharmacol Sin 4:342-343.
Based on the data provided herein, it is expected that actual dose
levels optimal for neuropathic pain utility in humans will require
ibudilast (as dispensed as Ketas.sup.R and other commercial generic
forms) dosage levels above 10 mg BID or TID.
[0165] By staining for GFAP immunoreactivity in spinal cord tissue
from rats experiencing neuropathic pain (CCI procedure), it was
shown that the astrocyte activation typically observed following
nerve injury was reduced following systemic (i.p.) administration
of ibudilast. Moreover, such reduction of GFAP immunoreactivity
correlated with ibudilast efficacy for reducing mechanical
allodynia.
Example 2
Effect of Ibudilast on Mechanical Allodynia in a Rat Chung Model of
Neuropathic Pain
[0166] The effect of ibudilast on mechanical allodynia in a rat
Chung model of neuropathic pain was assessed.
Methods
[0167] Test Agents. Haorui and Sigma ibudilast was formulated as
described above. Ibudilast was administered at 10 mg/kg twice
daily, (3.7 ml/kg of 2.7 mg/ml in 35% PEG/saline) i.p. each morning
(typically 8 am) and pm (typically 3 pm).
[0168] Animals: Pathogen-free adult male Wistar rats (150-200 g;
Elevage Janvier) were used in all experiments. Rats were housed in
temperature (23+/-3.degree. C.) and light (12:12 light: dark;
lights on at 0700 hr) controlled rooms with standard rodent chow
and water available ad libitum. Behavioral testing was performed
during the light cycle.
[0169] Chung model. Rats were anesthetized under isoflurane (4-5%
induction and 2-3% maintenance in 100% oxygen) and an incision at
the L4-S2 levels was performed to expose the left L5 and L6 spinal
nerves. A ligature was tied tightly around each nerve. The wound
was then sutured. The rats received an injection of clamoxil and
were allowed to recover. Sham controls were subjected to the same
surgical procedure except that the nerves were not ligated.
[0170] Behavioral Measures von Frey Test: The von Frey test was
performed as described above for the CCI model.
Studies and Results
[0171] Multi-day Study for Neuropathic Pain Efficacy: A 3-day
efficacy study was undertaken wherein the animals (n=3-4/group for
shams and 5/group for Chung animals) were administered 10 mg/kg
ibudilast or 35% PEG/saline vehicle twice daily and mechanical
allodynia was monitored at various time intervals post-dosing. The
+1 hr, +2 hr, and +4 hr time points were obtained following the am
dose. A pre-dose reading was acquired each day in order to assess
durability of efficacy.
[0172] As shown in FIG. 3, ibudilast treatment attenuated the
magnitude of allodynia in the Chung rats. Notably, sustained
attenuation was manifested at +2 hr post-administration starting on
the second day of b.i.d. dosing. Moreover, it is clear that within
two days of this b.i.d. regimen, the effect was already becoming
more sustained such that reversal of neuropathic pain was also
evident for as long as 16 hr (pre-dose reading) following ibudilast
treatment.
Conclusions
[0173] The results of the studies described herein using another
classic model of neuropathic pain indicate that systemic
administration of ibudilast to Chung rats attenuates mechanical
allodynia. Importantly, the somewhat transient nature of the
allodynia attenuation observed after a single administration
becomes long-lasting by the second day of a bid regimen.
Example 3
Effect of Ibudilast on Mechanical Allodynia in a Rat Model of
Taxol-Induced Neuropathic Pain
[0174] The effect of ibudilast on mechanical allodynia in a rat
model of taxol-induced neuropathic pain was assessed as described
below.
Methods
[0175] Test Agents: Ibudilast was formulated as described above.
Ibudilast was administered at 7.5 mg/kg (2.7 ml/kg of 2.8 mg/ml in
35% PEG/saline i.p. each morning (typically 8 am) and pm (typically
3 pm).
[0176] Animals: Pathogen-free adult male Sprague-Dawley rats
(280-350 g; Harlan Labs) were used in all experiments. Rats were
housed in temperature (23+/-3.degree. C.) and light (12:12 light:
dark; lights on at 0700 hr) controlled rooms with standard rodent
chow and water available ad libitum. Behavioral testing was
performed during the light cycle.
[0177] Taxol Model: Neuropathic pain was induced by administration
of 4 i.p. injections on alternate days (Day 0, 2, 4, and 6) of 1
mg/kg taxol (Paclitaxel.RTM., cumulative dose 4 mg/kg). Neuropathic
pain onset was maximal around day 19 post taxol administration (Day
0). Neuropathic pain onset was maximal around day 19 post taxol
administration (Day 0). Ibudilast or vehicle control treatment
initiated at either day 19 (treatment paradigm) or day 12
(prevention paradigm). Allodynia results were determined prior to
the morning administration of vehicle or ibudilast.
[0178] Behavioral Measures von Frey Test: The von Frey test was
performed within the sciatic or saphenous innervation area of the
hindpaws as previously described above for the CCI model. All
testing was conducted in the am prior to the morning dose of
ibudilast for that day.
Studies and Results
[0179] Multi-day Study for Neuropathic Pain Efficacy: 7.5 mg/kg
Ibudilast was administered twice daily for 7 days starting day 20
after the first taxol dose (Day 0). Mechanical allodynia was
assessed prior to the first dose of ibudilast each day.
[0180] As shown in FIG. 4, administration of ibudilast treatment
attenuated the magnitude of allodynia in rats administered taxol.
The b.i.d. regimen sustained attenuation of allodynia throughout
the dosing period as demonstrated by increased paw withdrawal
thresholds prior to daily dosing. Discontinuation of ibudilast
administration resulted in return of the rats to an allodynic state
within 1 day.
[0181] Prevention of Taxol-Induced Neuropathy: A second study was
performed identical in nature to the multi-day study described
above except that ibudilast or vehicle control administrations were
initiated on day 12 just as allodynia was becoming clearly evident.
Ibudilast therapy prevented the further neuropathy development and
attenuated the low level of allodynia to a level not significantly
different from the non-chemotherapy control animals.
Conclusions
[0182] The results of the studies described herein using a model of
neuropathic pain indicate that systemic administration of ibudilast
to rats administered taxol attenuates mechanical allodynia.
Attenuation of allodynia is sustained (i.e. apparent overnight to
the morning testing period) during b.i.d. administration with rats
returning to an allodynic state upon discontinuation of ibudilast
administration. Importantly, it was also shown in FIG. 4B that
ibudilast treatment could prevent the development of cancer
chemotherapy (taxol)-induced neuropathy (allodynia in this
example). Such observations with the taxol model of cancer
chemotherapy-induced neuropathic pain is expected to extend to
other cancer chemotherapeutics known to result in patient
neuropathies.
[0183] Mechanical allodynia is a common and devastating
complication of neuropathic pain in animal models and in humans
with chronic neuropathic pain. Hence, the results described herein
represent the first known disclosure of the therapeutic use of
ibudilast for the treatment of various types of chronic neuropathic
pain syndromes in mammals, particularly those syndromes in which
mechanical allodynia is a common symptom.
Example 4
Rat Ibudilast Plasma PK and Tissue Distribution
[0184] Ibudilast pharmacokinetics and distribution into plasma,
muscle, brain, and spinal cord was assessed as follows.
Methods
[0185] Test Agents. Ibudilast was prepared in 15% ethanol/saline.
Drug stability and concentration were validated by HPLC/MS/MS.
[0186] Animals: Pathogen-free adult male Sprague-Dawley rats
(280-350 g; Harlan Labs) were used in all experiments. Rats were
housed in temperature (23+/-3.degree. C.) and light (12:12 light:
dark; lights on at 0700 hr) controlled rooms with standard rodent
chow and water available ad libitum. Behavioral testing was
performed during the light cycle.
[0187] PK Analysis: Rats (n=3/group) were administered 5 mg/kg
ibudilast, i.p. and plasma, muscle, brain, and spinal cord were
harvested at 5, 15, 60, 180, and 420 min post administration.
[0188] Tissue Concentration Analysis: A solution of ibudilast
(Haorui) at 0.5 mg/ml in DMSO was used as the working stock. A
solution of ibudilast at 0.5 mg/ml in DMSO was prepared using the
powdered ibudilast provided with the study samples and used as the
working stock. Calibration standards in plasma were prepared by
diluting each 0.5 mg/ml stock 1 in 100 into rat plasma to 5000
ng/ml (5 .mu.l+495 .mu.l), then diluting further, to 2.29 ng/ml, by
3-fold serial dilution with plasma. Standards 3, 5 and 7 were used
as low, mid and high QC samples, respectively.
[0189] Calibration standards, QC and plasma study samples were
prepared for HPLC injection by precipitating 25 .mu.l of plasma
with 3.times. volumes (75 .mu.l) of ice cold acetonitrile
containing 50 ng/ml diphenhydramine and 100 ng/ml dextromethorphan
as the internal standards. Tissue study samples were prepared for
HPLC injection by adding 1 .mu.l of water per mg of tissue plus
3.times. volumes (relative to water) of ice cold acetonitrile
containing 50 ng/ml diphenhydramine and 100 ng/ml dextromethorphan
as the internal standards, then homogenized with an electric
homogenizer. Following centrifugation at 6100 g for 30 minutes, 40
.mu.l of each supernatant was diluted with 200 .mu.l of 0.2% formic
acid in water and analyzed by the following LC/MS/MS
conditions:
HPLC: Shimadzu VP System
Mobile Phase: 0.2% formic acid in water (A) and in methanol (B)
Column: 2.times.10 mm Peeke Scientific DuraGel G C.sub.18 guard
cartridge
Injection Volume: 100 .mu.l
Gradient: 5-95% B in 2 minutes after a 0.75 minute wash
Flow Rate: 400 .mu.l/min
Mass Spectrometer: Applied Biosystems/MDS SCIEX API 3000
Interface: TurboIonSpray (ESI) at 400.degree. C.
Ionization Mode: Positive Ion
Q1/Q3 Ions: 231.2/161.2 for ibudilast
Studies and Results
[0190] Intraperitoneal administration of ibudilast yields good
plasma concentrations which decline from the Cmax in a biphasic
manner. Ibudilast is well distributed to peripheral (e.g. muscle)
and central (e.g. brain and spinal cord) tissues. (FIG. 5A). The
maximal concentration (Cmax) in plasma and CNS tissues was .about.1
.mu.g/mL following i.p. administration of .about.5 mg/kg ibudilast
formulated as described. The elimination half-life ranged 100-139
min in all tissue compartments.
Conclusions
[0191] Based on the above, it can be seen that ibudilast is
well-distributed peripherally and centrally with tissue kinetics
following a single administration similar to that of the plasma
compartment. A PK study of ibudilast formulated in 35%
PEG400/saline and administered at 21 mg/kg orally to rats is
depicted in FIG. 5B. The formulation, dose and route were selected
based on our previous results demonstrating attenuation of
allodynia in CCI rats under such conditions. The pharmacokinetic
parameters derived from the plasma concentration vs time profile
are indicated in the table below the figure. Such parameters
therefore represent pharmacokinetic correlates with neuropathic
pain efficacy.
Example 5
A Prospective, Double-Blind, Randomized, Placebo-Controlled Human
Trial of Ibudilast in the Treatment of Neuropathic Pain
[0192] The purpose of the study is to compare the end of treatment
Visual Analog Scale of Pain Index (VASPI) scores with baseline and
compare the VASPI score changes among the treatment groups. Safety,
tolerability and pharmacokinetics are also assessed.
Method.
[0193] This is a double-blind study. The first 7 days of the study
consist of a single-blind placebo run-in period. On Study Day 2,
subjects are sequentially assigned to receive a single dose of
either 10 mg, 20 mg, 30 mg or 40 mg of ibudilast. Pharmacokinetic
samples are obtained on Study Day 2. VASPI scores are collected
daily. On Study Day 8, subjects who have a favorable response
during the run-in period as defined as a 30% change from baseline
in VASPI scores, are assigned placebo therapy for the next 14 days.
Subjects who did not respond during the run-in period are
randomized to receive either BID or TID therapy with ibudilast.
Three dose cohorts using 20 mg, 30 mg and 40 mg are used with 20
subjects enrolled in each cohort. Cohorts are filled in a
sequential order with the first group of subjects assigned to 20 mg
BID or TID, 2.sup.nd cohort assigned to 30 mg BID or TID and the 3
rd cohort of subjects assigned to 40 mg BID or TID. Dose escalation
to higher cohorts is contingent on acceptable safety and
tolerability observed in the lower dose cohorts. Adverse events,
clinical laboratory results and assessments using the NIH (or EU
equivalent) Toxicity Grading Scale are reported. To maintain the
blinding of the study medication, all subjects receive TID dosing
starting on Day 8 through Day 21.
[0194] Subjects are in-house on days that pharmacokinetic
parameters are obtained (Days 1, 2, 8, 9, 21 and 22).
[0195] Study population: Male or female subjects with diabetic
neuropathy or complex regional pain syndrome. Inclusion criteria
include: subjects who provide written informed consent, male or
female subjects aged 18 to 70 years, diagnosis of diabetic
neuropathy or complex regional pain syndrome of at least 6 months
duration, VASPI score of 4 or higher for at least 2 weeks prior to
the study. Female subjects of child-bearing potential have to be
either surgically sterile or using an effective method of
contraception. Female subjects of child-bearing potential must have
a negative pregnancy test on Study Day 1. Exclusion criteria
include subjects with a known hypersensitivity to ibudilast or its
components, subjects with any history of a condition which might
affect drug absorption, metabolism or excretion, subjects with a
history of mental illness, drug addiction, drug abuse or
alcoholism, subjects who donated blood in the past 90 days, or have
experienced difficulty in donating blood, subjects who have a
positive hepatitis B, HIV or drug screen test, female subjects who
are pregnant or nursing mothers, and subjects who have received an
investigational drug in the past 90 days.
[0196] Evaluations include safety, e.g., adverse events, clinical
laboratory evaluations, vital signs and 12-lead ECGs, and
pharmacokinetics.
[0197] Blood samples (1.5 mL) for the assay of ibudilast are
collected for the evaluation of plasma levels. Samples are frozen
at approximately (-20 or -70.degree. C.) prior to analysis.
TABLE-US-00001 TABLE Schedule of Subject Dosing and Evaluation
Single Dosing Screen Days Multiple Dosing (Day 0) Day 1 Day 2 3-7
Day 8 Day 9 Day 21 Day 22 Informed Consent X Medical History X
VASPI X X X X X X Neuropathic Pain Scale X X X X X X Physical Exam
X X Clinical Labs (CBC, Chemistry, X X Urinalysis) Pregnancy Test X
X Hepatitis B, HIV & drug screen X LFTs only X ECG X X X Vital
Signs (blood pressure and X X X X X X heart rate) Dosing* X X X X X
X PK sample Times Pre-dose-Time 0 (e.g. 8:00) X X X X X 30 minute
(e.g. 8:30) X X 1 hour (e.g. 9:00) X X X X 2 hours (e.g. (10:00) X
X X X 4 hours (e.g. 12:00) X X X X 6 hours (e.g. 14:00) X X 8 hours
(e.g. 16:00) X X X X 12 hours (e.g. 20:00) X X 16 hours (e.g.
24:00) 24 hours (e.g. 8:00 D7) X 28 hours (e.g. 12:00 D7) X 32
hours (e.g. 16:00 D7) X Adverse Events X X X X X X Concomitant
Medications X X X X X X *Days 1-7 single doses @ 8:00 Days 8-20 BID
dosing @ 8:00 and 20:00, TID dosing @ 8:00, 14:00 and 20:00) Blood
draws occur prior to dosing. Meals are given @ 9:00, 13:00, and
18:00)
* * * * *